Tandem mass spectrometry (MS-MS) employs separation of parent ions in a first mass spectrometer (MS1), fragmentation of separated species, and mass analysis of fragment ions in a second mass spectrometer (MS2) for compound identification and structural studies. The recent application of tandem mass spectrometry in life sciences brought the challenge of analyzing extremely complex mixtures, i.e., mixtures with up to millions of components with an ultimate requirement for nine orders of dynamic range. Such analyses may require an upfront chromatography for separating an original mixture into hundreds of fractions. Still, mixtures remain extremely complex, which stresses the requirements for sensitivity, dynamic range, resolution, mass accuracy, speed, and/or throughput of MS-MS.
Time-of-flight mass spectrometers (TOF MS) are widely used in analytical chemistry for identification and quantitative analysis of mixtures. TOF MS have a high potential for use in MS-MS because TOF MS offer intrinsically parallel analysis of all mass and recently achieved high resolving power. GB2403063 and WO2005001878 disclose a planar multi-reflecting TOF (MR-TOF) with a set of periodic lenses for spatial confinement of ion packets. An example commercial implementation of a MR-TOF, Citius IIR™ LECO Corp., demonstrates that the extended folded ion path improves resolution to R=100,000 level. Multiple improvements of MR-TOF are proposed in U.S. Pat. No. 7,326,925 (curved isochronous ion injection), U.S. Pat. No. 7,772,547 (double orthogonal injection), WO2010008386 (quasi-planar mirrors for drift focusing at reduced aberrations), WO2011086430 (cylindrical analyzers), and WO2013063587 (high-order isochronous ion mirrors). WO2011135477 discloses a frequent encoded pulsing of an orthogonal accelerator.
TOF MS have been employed for tandem time-of-flight mass spectrometers (TOF-TOF) when used with intrinsically pulsed ion sources, like MALDI. U.S. Pat. No. 5,202,563 discloses a tandem time-of-flight mass spectrometer (TOF-TOF) composed of two singly reflecting TOF MS coupled via a collisional ion dissociation (CID) cell. A timed ion selector (TIS) passes one parent ion mass per every TOF1 shot. Ions are decelerated in-front of a CID cell and then fragment ions are reaccelerated in a pulsed or continuous manner. U.S. Pat. No. 6,770,870 discloses a delayed fragment extraction for ion selection past CID cell. GB2390935, U.S. Pat. No. 7,385,187, and U.S. Pat. No. 7,196,324B disclose an “all-mass” TOF-TOF instrument for parallel acquisition of fragment spectra for all parent ions. The principle on nested time scales between TOF1 and TOF2 stages, however, does limit resolution of the second stage. US20070029473 and U.S. Pat. No. 7,385,187 disclose a tandem of two multi-reflecting TOF MS, coupled via a CID or SID cell, though operating sequentially, i.e., with selection of single parent specie per shot. WO2010138781 discloses a tandem of singly reflecting TOF analyzers while claiming selection of multiple parent ions per single ion source ejection, though not disclosing multiplexing algorithms.
Summarizing the above, the prior art TOF-TOF tandems do not yet reach parallel “all-mass” analysis while employing high resolution multi-reflecting TOF analyzers at both stages. Therefore, there is a need for improving resolution, sensitivity, speed, and dynamic range of TOF-TOF tandems. There is also a need for unambiguous encoding method for converting the proclaimed goal of all-mass parallel tandem analysis into practical method and instrument.